Open AccessNuclear Receptor DHR96 Acts as a Sentinel for Low Cholesterol Concentrations in Drosophila melanogaster
Author(s) -
Mattéa Bujold,
Akila Gopalakrishnan,
Emma Nally,
Kirst King-Jones
Publication year - 2010
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01327-09
Subject(s) - biology , cholesterol , liver x receptor , mutant , drosophila melanogaster , homeostasis , nuclear receptor , microbiology and biotechnology , mutation , genetics , gene , biochemistry , transcription factor
All eukaryotic cells have to maintain cholesterol concentrations within defined margins in order to function normally. Perturbing cholesterol homeostasis can result in a wide range of cellular and systemic defects, including cardiovascular diseases, as well as Niemann-Pick and Tangier diseases. Here, we show thatDHR96 is indispensable for mediating the transcriptional response to dietary cholesterol and that it acts as a key regulator of the Niemann-Pick type C gene family, as well as of other genes involved in cholesterol uptake, metabolism, and transport.DHR96 mutants are viable and phenotypically normal on a standard medium but fail to survive on diets that are low in cholesterol.DHR96 mutants have aberrant cholesterol levels, demonstrating a defect in maintaining cholesterol homeostasis. Remarkably, we found that a high-cholesterol diet phenocopied the genomic profile of theDHR96 mutation, indicating that DHR96 resides at the top of a genetic hierarchy controlling cholesterol homeostasis in insects. We propose a model whereby DHR96 is activated when cellular cholesterol concentrations drop below a critical threshold in order to protect cells from severe cholesterol deprivation.